Antibodies Raised Against an Aß Oligomer Mimic Recognize Pathological Features in Alzheimer's Disease and Associated Amyloid-Disease Brain Tissue.

Antibodies that target the ß-amyloid peptide (Aß) and its associated assemblies are important tools in Alzheimer's disease research and have emerged as promising Alzheimer's disease therapies. This paper reports the creation and characterization of a triangular Aß trimer mimic composed of Aß17-36 ß-hairpins and the generation and study of polyclonal antibodies raised against the Aß trimer mimic. The Aß trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the Aß trimer mimic shares characteristics with oligomers of full-length Aß. X-ray crystallography elucidates the structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer. SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution. Cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Immunostaining studies on brain slices from people who lived with Alzheimer's disease and people who lived with Down syndrome reveal that the polyclonal antibodies raised against the Aß trimer mimic recognize pathological features including different types of Aß plaques and cerebral amyloid angiopathy.

Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with remarkable differences evident between individuals at the molecular level. Here we present a transcriptomic survey of AD using spatial transcriptomics (ST) and single-nucleus RNA-seq in cortical samples from early-stage AD, late-stage AD, and AD in Down Syndrome (AD in DS) donors. Studying AD in DS provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. Our analysis revealed spatial and cell-type specific changes in disease, with broad similarities in these changes between sAD and AD in DS. We performed additional ST experiments in a disease timecourse of 5xFAD and wildtype mice to facilitate cross-species comparisons. Finally, amyloid plaque and fibril imaging in the same tissue samples used for ST enabled us to directly link changes in gene expression with accumulation and spread of pathology.

Inclusion body myositis: evolving concepts.

PURPOSE OF REVIEW: To discuss recent developments in our understanding of epidemiology, diagnostics, biomarkers, pathology, pathogenesis, outcome measures, and therapeutics in inclusion body myositis (IBM). RECENT FINDINGS: Recent epidemiology data confirms a relatively higher prevalence in the population aged above 50 years and the reduced life expectancy. Association with cancer and other systemic disorders is better defined. The role of magnetic resonance imaging (MRI) and ultrasound in diagnosis as well as in following disease progression has been elucidated. There are new blood and imaging biomarkers that show tremendous promise for diagnosis and as outcome measures in therapeutic trials. Improved understanding of the pathogenesis of the disease will lead to better therapeutic interventions, but also highlights the importance to have sensitive and responsive outcome measures that accurately quantitate change. SUMMARY: There are exciting new developments in our understanding of IBM which should lead to improved management and therapeutic options.

A clinicopathologic study of malignancy in VCP-associated multisystem proteinopathy.

BACKGROUND: Valosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin-proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma. Since MSP1 is caused by gain of function variants in the VCP gene, we hypothesized our patients would show increased risk for developing malignancies. We describe cases of 3 rare malignancies and 4 common cancers from a retrospective dataset. RESULTS: Upon surveying 106 families with confirmed VCP variants, we found a higher rate of rare tumors including malignant peripheral nerve sheath tumor, anaplastic pleomorphic xanthoastrocytoma and thymoma. Some of these subjects developed cancer before displaying other classic VCP disease manifestations. We also present cases of common cancers; however, we did not find an increased rate compared to the general population. This could be related to the early mortality associated with this disease, since most patients die in their 50-60 s due to respiratory failure or cardiomyopathy which is earlier than the age at which most cancers appear. CONCLUSION: This is the first study that expands the phenotype of VCP disease to potentially include rare cancers and highlights the importance of further investigation of the role of VCP in cancer development. The results of this study in VCP disease patients suggest that patients may be at an increased risk for rare tumors. A larger study will determine if patients with VCP disease develop cancer at a higher rate than the general population. If that is the case, they should be followed up more frequently and screened for recurrence and metastasis of their cancer.

Dementia is associated with medial temporal atrophy even after accounting for neuropathologies.

Brain atrophy is associated with degenerative neuropathologies and the clinical status of dementia. Whether dementia is associated with atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies. We used data from National Alzheimer's Coordinating Center (n = 129) and Alzheimer's Disease Neuroimaging Initiative (n = 47) participants with suitable in vivo 3D-T1w MRI and autopsy data. We determined dementia status at the visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer's disease neuropathology, hippocampal sclerosis, Lewy bodies, cerebral amyloid angiopathy and atherosclerosis. Voxel-based morphometry identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analysed. We used multiple linear regression models adjusted for neuropathologies and demographic variables. We also examined models with dementia and Clinical Dementia Rating sum of the boxes as the outcome and explored the potential mediating effect of medial temporal lobe structure volumes on the relationship between pathology and cognition. We found strong associations for dementia with volumes of the hippocampus, amygdala and parahippocampus (semi-partial correlations ≥ 0.28, P < 0.0001 for all regions in National Alzheimer's Coordinating Center; semi-partial correlations ≥ 0.35, P ≤ 0.01 for hippocampus and parahippocampus in Alzheimer's Disease Neuroimaging Initiative). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%). We also found that the volumes of the medial temporal lobe structures contributed towards explaining the variance in Clinical Dementia Rating sum of the boxes (ranging from 5% to 9%) independent of neuropathologies and partially mediated the association between Alzheimer's disease neuropathology and cognition. Even after accounting for the most common neuropathologies, dementia still had among the strongest associations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to the clinical status of dementia rather than Alzheimer's disease or other neuropathologies, with the potential exception of hippocampal sclerosis.

Polymerase Chain Reaction (PCR)-Negative Herpes Simplex Virus (HSV) Encephalitis in a 62-Year-Old Woman With p-ANCA Vasculitis.

We present the case of a 62-year-old woman with a past medical history significant for p-ANCA vasculitis (on immunosuppression) who was found to have polymerase chain reaction (PCR)-negative herpes simplex virus (HSV) encephalitis. We also present a review of all identifiable reports of PCR-negative HSV encephalitis in the past 20 years. To our knowledge, this is the first case of PCR-negative HSV encephalitis in a patient with p-ANCA vasculitis and the thirteenth overall in this timeframe. The patient presented with new-onset fever, encephalopathy, and a first-in-lifetime focal motor seizure progressing to status epilepticus. Cerebrospinal fluid (CSF) PCR was negative for HSV on three separate instances between the first and thirteenth days since symptom onset, and the CSF profile was not typical for HSV encephalitis. The patient underwent a brain biopsy, which confirmed the presence of HSV. She continued to worsen despite aggressive seizure control and six days of empiric acyclovir. Unfortunately, she expired despite the reinitiation of acyclovir. When faced with the classical features of encephalitis in the immunocompromised, the suspicion of HSV should remain high despite negative PCR results. The completion of a full course of acyclovir in the absence of clinical improvement should be considered.

Mixed gangliocytoma-pituitary adenoma in MEN1 syndrome: A case report and literature review.

Pituitary adenoma is one of the three most common neoplasms described in multiple endocrine neoplasia type 1 (MEN1), and patients with pituitary adenoma occupies 30-50% of those with MEN1-related tumor. Mixed gangliocytoma-pituitary adenoma (MGPA) is a rare clinical entity in which gangliomatous cells are intermixed with adenomatous cells. This tumor has been estimated to account for 0.52-1.26% of all pituitary tumors. We report a rare case of MGPA in a patient with MEN1. A retrospective chart review was conducted on a patient with MEN1 diagnosed with MGPA in 2019 at a single tertiary academic medical center. A review of the literature was performed on MGPA and pituitary adenoma in MEN1. MGPA is rare, with only 174 cases previously reported in the literature and only three prior case reported in a patient with MEN1. There are multiple hypotheses regarding their pathogenesis, and it is unclear whether the MEN1 gene (menin) plays a role in the pathogenesis of MGPA. This tumor in MEN1 is a rare clinical entity of unknown etiology. Further studies are required with difficulty due to its low incidence.

Post-mortem Examination of the Nervous System: Fresh versus Fixed.

BACKGROUND: Post-mortem examination of the nervous system is a complex task that culminates in "brain cutting". It relies on expertise in neuroanatomy, clinical neurosciences, neuroimaging and experience in order to recognise the most subtle abnormalities. Like any specialist examination in medicine, it warrants formal training, a standardised approach and optimal conditions. Revelations of aberrant tissue retention practices of a select few pathologists (e.g. Goudge, Liverpool and Alder Hey inquiries) and a motivated sociopolitical climate led some Canadian jurisdictions to impose broad restrictions on tissue retention. This raised concerns that nervous system examinations for diagnosis, education and research were at risk by limiting examinations to the fresh or incompletely fixed state. Professional experience indicates that cutting an unfixed or partly fixed brain is inferior. METHODS: To add objectivity and further insight we sought the expert opinion of a group of qualified specialists. Canadian neuropathologists were surveyed for their opinion on the relative merits of examining brains in the fresh or fully fixed state. RESULTS: A total of 14 out of 46 Canadian neuropathologists responded (30%). In the pervasive opinion of respondents, cutting and sampling a brain prior to full fixation leads to a loss of diagnostic accuracy, biosafety and academic deliverables. CONCLUSIONS: Brain cutting in the fresh state is significantly impaired along multiple dimensions of relevance to a pathologist's professional roles and obligations.

Pigmented ependymoma, a tumor with predilection for the middle-aged adult: case report with methylation classification and review of 16 literature cases.

Ependymomas have rarely been described to contain pigment other than melanin, neuromelanin, lipofuscin or a combination. In this case report, we present a pigmented ependymoma in the fourth ventricle of an adult patient and review 16 additional cases of pigmented ependymoma from the literature. A 46-year-old female showed up with hearing loss, headaches, and nausea. Magnetic resonance imaging revealed a 2.5 cm contrast-enhancing cystic mass in the fourth ventricle, which was resected. Intraoperatively, the tumor appeared grey-brown, cystic, and was adherent to the brainstem. Routine histology revealed a tumor with true rosettes, perivascular pseudorosettes and ependymal canals consistent with ependymoma, but also showed chronic inflammation and abundant distended pigmented tumor cells that mimicked macrophages in frozen and permanent sections. The pigmented cells were positive for GFAP and negative for CD163 consonant with glial tumor cells. The pigment was negative for Fontana-Masson, positive for Periodic-acid Schiff and autofluorescent, which coincide with characteristics of lipofuscin. Proliferation indices were low and H3K27me3 showed partial loss. H3K27me 3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates the tri-methylation of lysine 27 on histone H3 protein. This methylation classification was compatible with a posterior fossa group B ependymoma (EPN_PFB). The patient was clinically well without recurrence at three-month post-operative follow-up appointment. Our analysis of all 17 cases, including the one presented, shows that pigmented ependymomas are most common in the middle-aged with a median age of 42 years and most have a favorable outcome. However, one patient that also developed secondary leptomeningeal melanin accumulations died. Most (58.8%) arise in the 4th ventricle, while spinal cord (17.6%) and supratentorial locations (17.6%) were less common. The age of presentation and generally good prognosis raise the question of whether most other posterior fossa pigmented ependymomas may also fall into the EPN_PFB group, but additional study is required to address that question.

Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer's disease.

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome.

The Mini-Craniotomy for cSDH Revisited: New Perspectives.

Background: Chronic subdural hematomas (cSDH) are increasingly prevalent worldwide with the increased aging population and anticoagulant use. Different surgical, medical, and endovascular treatments have had varying success rates. Primary neurosurgical interventions include burr hole drainage of the cSDH and mini-craniotomies/craniotomies with or without fenestration of the inner membrane. A key assessment of the success or failure of cSDH treatments has been symptomatic recurrence rates which have historically ranged from 5 to 30%. Pre-operative prediction of the inner subdural membrane by CT scan was used to guide our decision to perform mini-craniotomies. Release of the inner membrane facilitates the expansion of the brain and likely improves glymphatic flow. Methods: Consecutive mini-craniotomies (N = 34) for cSDH evacuation performed by a single neurosurgeon at a quaternary academic medical center/Level I trauma center from July 2018-September 2020 were retrospectively reviewed. Patient characteristics [age, gender, presenting GCS, GOS, initial CTs noting the inner subdural membrane, midline shift (MLS), cSDH width, inner membrane fenestration, cSDH recurrence, post-operative seizures, infections, length of stay] were extracted from the EMR. Results: Twenty nine patients had mini-craniotomies as primary treatment of the cSDH. Mean age = 68.9 ± 19.7 years (range 22-102), mean pre-operative GCS = 14.5 ± 1.1, mean MLS = 6.75 ± 4.2 mm, and mean maximum thickness of cSDH = 17.7 ± 6.0 mm. Twenty four were unilateral, five bilateral, 34 total craniotomies were performed. Thirty three had inner membrane signs on pre-operative head CTs and an inner subdural membrane was fenestrated in all cases except for the one craniotomy that didn't show these characteristic CT findings. Mean operating time = 79.5 ± 26.0 min. Radiographic and clinical improvement occurred in all patients. Mean improvement in MLS = 3.85 ± 2.69. There were no symptomatic recurrences, re-operations, surgical site infections, or deaths during the 6 months of follow-up. One patient was treated for post-operative seizures with AEDs for 6 months. Conclusion: Pre-operative CT scans demonstrating inner subdural membranes may guide one to target the treatment to allow release of this tension band. Mini-craniotomy with careful fenestration of the inner membrane is very effective for this. Brain re-expansion and re-establishment of normal brain interstitial flow may be important in long term outcomes with cSDH and may be related to the recent interests in brain glymphatics and dural lymphatics.

Surgical management of a rare myxopapillary ependymoma of the gluteal region: A case report.

BACKGROUND: Ependymomas are rare tumors originating from neuroepithelial cells lining the wall of the ventricles or central canal of the spinal cord. While these tumors mainly occur within the central nervous system (CNS), there are occasional reports in children and young adult patients with a primary tumor occurrence outside of the CNS. Ependymomas of the sacrococcygeal region have been infrequently described in the literature with no standard of care established. We present a case report and review of the literature regarding this rare entity. CASE DESCRIPTION: A 24-year-old woman presented with right gluteal pain worsened by sitting and a palpable soft tissue mass of the sacrococcygeal region. Magnetic resonance imaging revealed a 3.7 cm cystic mass centered in the right gluteal region. She underwent a biopsy at an outside institution, with histology revealing myxopapillary ependymoma. The patient was referred to our hospital and underwent an interdisciplinary neurosurgical and orthopedic oncology en bloc resection of the ependymoma, which intraoperatively appeared to originate from the coccygeal nerve. CONCLUSION: In the present report, the authors demonstrate that a myxopapillary ependymoma may present as an isolated gluteal mass attached to the coccygeal nerve, without frank CNS involvement. Furthermore, an interdisciplinary approach to surgical resection of this lesion appears to represent an effective treatment modality.

Neuropathology of COVID-19 (neuro-COVID): clinicopathological update.

Coronavirus disease 2019 (COVID-19) is emerging as the greatest public health crisis in the early 21stcentury. Its causative agent, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is an enveloped single stranded positive-sense ribonucleic acid virus that enters cells via the angiotensin converting enzyme 2 receptor or several other receptors. While COVID-19 primarily affects the respiratory system, other organs including the brain can be involved. In Western clinical studies, relatively mild neurological dysfunction such as anosmia and dysgeusia is frequent (~70-84%) while severe neurologic disorders such as stroke (~1-6%) and meningoencephalitis are less common. It is unclear how much SARS-CoV-2 infection contributes to the incidence of stroke given co-morbidities in the affected patient population. Rarely, clinically-defined cases of acute disseminated encephalomyelitis, Guillain-Barré syndrome and acute necrotizing encephalopathy have been reported in COVID-19 patients. Common neuropathological findings in the 184 patients reviewed include microglial activation (42.9%) with microglial nodules in a subset (33.3%), lymphoid inflammation (37.5%), acute hypoxic-ischemic changes (29.9%), astrogliosis (27.7%), acute/subacute brain infarcts (21.2%), spontaneous hemorrhage (15.8%), and microthrombi (15.2%). In our institutional cases, we also note occasional anterior pituitary infarcts. COVID-19 coagulopathy, sepsis, and acute respiratory distress likely contribute to a number of these findings. When present, central nervous system lymphoid inflammation is often minimal to mild, is detected best by immunohistochemistry and, in one study, indistinguishable from control sepsis cases. Some cases evince microglial nodules or neuronophagy, strongly supporting viral meningoencephalitis, with a proclivity for involvement of the medulla oblongata. The virus is detectable by reverse transcriptase polymerase chain reaction, immunohistochemistry, or electron microscopy in human cerebrum, cerebellum, cranial nerves, olfactory bulb, as well as in the olfactory epithelium; neurons and endothelium can also be infected. Review of the extant cases has limitations including selection bias and limited clinical information in some cases. Much remains to be learned about the effects of direct viral infection of brain cells and whether SARS-CoV-2 persists long-term contributing to chronic symptomatology.

Expanding the Phenotype of Frontotemporal Lobar Degeneration With FUS-Positive Pathology (FTLD-FUS).

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is an uncommon cause of frontotemporal dementia characterized by fused in sarcoma-positive inclusions. It is classified as a subtype of frontotemporal lobar degeneration with FUS pathology. Cases with aFTLD-U pathology typically display an early onset of symptoms and severe psychobehavioral changes in the absence of significant aphasia, cognitive-intellectual dysfunction or motor features. This phenotype is regarded as being sufficiently unusual and consistent as to allow antemortem diagnosis with a high degree of accuracy. In this report, we describe 2 cases with aFTLD-U pathology that broaden the associated phenotype to include later age of onset, milder behavioral abnormalities and early memory and language impairment.

Epithelioid Osteoblastoma of the Temporal Bone: A Case Report.

BACKGROUND: Epithelioid osteoblastoma of the cranium is extremely rare and can mimic other etiologies on radiographic imaging, pathology, and symptomatology. CASE DESCRIPTION: An 18-year-old male patient had a 3-week history of a palpable left temporal mass. Magnetic resonance imaging revealed a large, extra-axial, hypervascular mass in the left temporal bone, with bony erosion and intracranial extension. The patient underwent surgical near gross-total resection of the mass. Initial frozen microscopic examination of the tumor was inconclusive. The postoperative course was uneventful, and the patient was discharged a few days later. Final pathology confirmed the diagnosis of epithelioid osteoblastoma. CONCLUSIONS: Epithelioid osteoblastoma of the skull base is exceedingly rare but should be included in the differential diagnoses of all extra axial tumors. Preoperative radiographic clues are limited, and final diagnosis relies solely on accurate pathologic examination. A diagnosis of epithelioid osteoblastoma should be considered for all cranial bone-based tumors, as an incorrect diagnosis of another radiographic and histologic mimic could lead to the patient receiving unnecessary and harmful neoadjuvant/adjuvant chemotherapy or radiotherapy.

Clinicopathologic features and pathogenesis of melanocytic colonization in atypical meningioma.

Only two prior cases of benign dendritic melanocytes colonizing a meningioma have been reported. We add a third case, describe clinicopathologic features shared by the three, and elucidate the risk factors for this very rare phenomenon. A 29 year-old Hispanic woman presented with headache and hydrocephalus. MRI showed a lobulated enhancing pineal region mass measuring 41 mm in greatest dimension. Subtotal resection of the mass demonstrated an atypical meningioma, WHO grade II, and the patient subsequently underwent radiotherapy. She presented 4 years later with diplopia, and MRI showed an enhancing extra-axial mass measuring 47 mm in greatest dimension and centered on the tentorial incisura. Subtotal resection showed a brain-invasive atypical meningioma with melanocytic colonization. The previous two cases in the literature were atypical meningiomas, one of which was also brain invasive. Atypical meningiomas may be at particular risk for melanocytic colonization as they upregulate molecules known to be chemoattractants for melanocytes. We detected c-Kit expression in a minority of the melanocytes as well as stem cell factor and basic fibroblast growth factor in the meningioma cells, suggesting that mechanisms implicated in normal melanocyte migration may be involved. In some cases, brain invasion with disruption of the leptomeningeal barrier may also facilitate migration from the subarachnoid space into the tumor. Whether there is low-level proliferation of the dendritic melanocytes is unclear. Given that all three patients were non-Caucasian, meningiomas in persons and/or brain regions with increased dendritic melanocytes may predispose to colonization. The age range spanned from 6 years old to 70 years old. All three patients were female. The role of gender and estrogen in the pathogenesis of this entity remains to be clarified. Whether melanocytic colonization may also occur in the more common Grade I meningiomas awaits identification of additional cases.

Q Fever Presented as a Large Retroperitoneal Pseudotumoral Mass.

BACKGROUND: Q fever is an infection caused by Coxiella burnetii, an intracellular organism. Acute infection is most often a benign and asymptomatic process; however, some individuals may go on to develop subacute and persistent localized symptomatic Q fever. As such, the clinical and histopathologic findings of Q fever are widely variable and may be missed if clinical suspicion is not high. CASE PRESENTATION: Herein we report the first case of C. burnetii infection presenting as an isolated retroperitoneal mass. A 61-year-old male underwent axillary-bifemoral bypass surgery. His postoperative course was complicated by the discovery of a large retroperitoneal mass. CONCLUSION: Clinical and histopathologic findings of Coxiella burnetii infection are variable and can be deceiving. These are often nonspecific, especially in its persistent localized infectious stages.

Early experience with formalin-fixed paraffin-embedded (FFPE) based commercial clinical genomic profiling of gliomas-robust and informative with caveats.

BACKGROUND: Commercial targeted genomic profiling with next generation sequencing using formalin-fixed paraffin embedded (FFPE) tissue has recently entered into clinical use for diagnosis and for the guiding of therapy. However, there is limited independent data regarding the accuracy or robustness of commercial genomic profiling in gliomas. METHODS: As part of patient care, FFPE samples of gliomas from 71 patients were submitted for targeted genomic profiling to one commonly used commercial vendor, Foundation Medicine. Genomic alterations were determined for the following grades or groups of gliomas; Grade I/II, Grade III, primary glioblastomas (GBMs), recurrent primary GBMs, and secondary GBMs. In addition, FFPE samples from the same patients were independently assessed with conventional methods such as immunohistochemistry (IHC), Quantitative real-time PCR (qRT-PCR), or Fluorescence in situ hybridization (FISH) for three genetic alterations: IDH1 mutations, EGFR amplification, and EGFRvIII expression. RESULTS: A total of 100 altered genes were detected by the aforementioned targeted genomic profiling assay. The number of different genomic alterations was significantly different between the five groups of gliomas and consistent with the literature. CDKN2A/B, TP53, and TERT were the most common genomic alterations seen in primary GBMs, whereas IDH1, TP53, and PIK3CA were the most common in secondary GBMs. Targeted genomic profiling demonstrated 92.3%-100% concordance with conventional methods. The targeted genomic profiling report provided an average of 5.5 drugs, and listed an average of 8.4 clinical trials for the 71 glioma patients studied but only a third of the trials were appropriate for glioma patients. CONCLUSIONS: In this limited comparison study, this commercial next generation sequencing based-targeted genomic profiling showed a high concordance rate with conventional methods for the 3 genetic alterations and identified mutations expected for the type of glioma. While it may not be feasible to exhaustively independently validate a commercial genomic profiling assay, examination of a few markers provides some reassurance of its robustness. While potential targeted drugs are recommended based on genetic alterations, to date most targeted therapies have failed in glioblasomas so the usefulness of such recommendations will increase with development of novel and efficacious drugs.

A novel association of biventricular cardiac noncompaction and diabetic embryopathy: case report and review of the literature.

Diabetic embryopathy refers to a constellation of congenital malformations arising in the setting of poorly controlled maternal diabetes mellitus. Cardiac abnormalities are the most frequently observed findings, with a 5-fold risk over normal pregnancies. Although a diverse spectrum of cardiac defects has been documented, cardiac noncompaction morphology has not been associated with this syndrome. In this report, we describe a novel case of biventricular cardiac noncompaction in a neonate of a diabetic mother. The patient was a late preterm female with right anotia, caudal dysgenesis, multiple cardiac septal and aortic arch defects, and biventricular cardiac noncompaction. Examination of both ventricles demonstrated spongy myocardium with increased myocardial trabeculation greater than 50% left ventricular thickness and greater than 75% right ventricular thickness, with hypoplasia of the bilateral papillary muscles, consistent with noncompaction morphology. Review of the literature highlights the importance of gene expression and epigenomic regulation in cardiac embryogenesis.